Multiple stimulus reversible hydrogels

ABSTRACT

A polymeric solution capable of gelling upon exposure to a critical minimum value of a plurality of environmental stimuli is disclosed. The polymeric solution may be an aqueous solution utilized in vivo and capable of having the gelation reversed if at least one of the stimuli fall below, or outside the range of, the critical minimum value. The aqueous polymeric solution can be used either in industrial or pharmaceutical environments. In the medical environment, the aqueous polymeric solution is provided with either a chemical or radioisotopic therapeutic agent for delivery to a specific body part. The primary advantage of the process is that exposure to one environmental stimuli alone will not cause gelation, thereby enabling the therapeutic agent to be conducted through the body for relatively long distances without gelation occurring.

[0001] This invention was made with Government support under ContractNo. DE-AC06-76RL01830 awarded by the U.S. Department of Energy. The U.S.Government has certain rights in the invention.

FIELD

[0002] The present invention relates in general to reversible gelcompounds in which gelation is the result of response to a plurality ofenvironmental stimuli. More particularly, the present invention isdirected to polymeric solutions which gel in response to exposure to acritical minimum value of at least two environmental stimuli, such as invivo stimuli found in human or other mammalian bodies. The gelationresponse can be reversed by reducing the value of at least one of suchenvironmental stimuli to less than (or outside the range of) thecritical minimum value.

BACKGROUND

[0003] The use of reversible gelling compounds is well known in the art.In the context of this art, “gel” means a form of material between theliquid and solid state that consists of physically crosslinked networksof long polymer molecules with liquid molecules trapped within thenetwork—a three-dimensional network swollen by a solvent. If the solventis water, the gel is termed a “hydrogel”.

[0004] Gels may be classified as either a chemical gel or a physicalgel. The former are formed by chemical covalent bonds, resulting in aproduct called covalently cross-linked gels, and are not reversible. Thelatter are formed by secondary physical forces, such as hydrogen bondingor hydrophobic or charge interactions, and are reversible.

[0005] Commercially available block copolymers of poly(ethyleneoxide-b-propylene oxide-b-ethylene oxide) (PEO/PPO/PEO; Pluronics (BASF,Mount Olive, NJ) or Poloxamers (ICI) are the best known examples ofreversible, thermally gelling polymers. PEO/PPO/PEO copolymers are afamily of more than 30 different nonionic surfactants, covering a widerange of liquids, solids and pastes with molecular weights ranging fromabout 1000 to 14,000. Concentrated solutions of PEO/PPO/PEO copolymersform reversible gels at high temperatures and revert to liquid stateupon lowering of temperature. Gelation temperature depends on polymercomposition and solution concentration.

[0006] Aqueous solutions of PEO/PPO/PEO copolymers demonstrate phasetransitions from sol to gel (low temperature sol-gel boundary) and gelto sol (high temperature gel-sol boundary) with monotonically increasingtemperature when the polymer concentration is above a minimum criticalvalue. The mechanism of gelation of PEO/PPO/PEO copolymers is stilluncertain.

[0007] Thermoreversible gels are also formed by several naturallyoccurring polymers such as gelatin (a protein prepared from partialhydrolysis of collagen), polysaccharides such as agarose, amylopectin,carrageenans, Gellan™, and the like. All of this class of biopolymersform hydrogels when cooled. By contrast, cellulose derivatives gel by adifferent mechanism: they are sols at low temperatures and become gelsat high temperatures. The sol-gel transition temperature is affected bysubstitutions at the hydroxyl group of cellulose.

[0008] Novel biodegradable triblock copolymers of polyethylene glycoland poly(lactic/glycolic acid)(PEG/PLGA/PEG) were developed, and asaqueous solutions exhibit sol to gel transition at body temperature. Anonresorbable thermoreversible gel based on copolymers ofN-isopropylacrylamide with acrylic acid (poly(NiPAAm-co-AAc)) have beendeveloped, and demonstrate reversible sol-to-gel transition atphysiological temperature ranges due to lower critical solutiontemperatures exhibited by polymers of the N-isopropylacrylamide.

[0009] As an example of a different gelling mechanism, charged, watersoluble polymers may form reversible gels in response to pH change insolution. For example, chitosan solutions exhibit a sol-to-geltransition at a pH of about 7.0, when pH changes from slightly acidic toneutral. The pH-triggered transition is slower than the transitioncaused by changes in temperature.

[0010] Chemically cross-linked gels are used extensively as matrices inchromatography and electrophoreses analytical methods to separatemolecules according to molecular weight and charge. Additionally,efforts have been made to deliver drugs to human patients via reversiblygelling polymers, as well as topical applications and for ophthalmicdelivery of therapeutic agents. It is known to use copolymer polyolswhich are available commercially under the trade name Pluronic™, asdescribed in U.S. Pat. No. 4,188,373.

[0011] In-situ gelling compounds have been proposed for use inimplantation of drug delivery systems (for example, in cancertreatment), as well as injectable matrices for tissue engineering.Stimulus induced in-vivo gelation is a process that produces no toxicpolymerization residues and results in no heat generation.

[0012] For example, U.S. Pat. No. 5,252,318 discloses a reversiblygelling aqueous composition that undergoes significant viscosity changesto simultaneous changes in both temperature and pH. The '318 compositionis comprised of a combination of at least two separate and distinctreversibly gelling polymers—one of which is temperature sensitive (suchas methyl cellulose or block copolymers of polyoxyethylene andpolyoxypropylene) and the other being pH sensitive (such as apolyacrylic acid). The composition is intended for use as dropinstillable, oral and injectable drug delivery vehicles, and fortopically applied lubricants, wetting agents and cleaning agents.

[0013] Other approaches to injectable polymers have includedsingle-stimulus polymers, as for example in U.S. Pat. No. 5,939,485.Gelation of the aqueous polymer solution is responsive to a change in asingle environmental stimulus, such as temperature, pH or ionicstrength.

[0014] U.S. Pat. No. 4,732,930 discloses a chemically cross-linked gelcomposition comprised of a polymerized product that is obtained bypolymerization of isopropylacrylamide monomer, a source of metal ions, acrosslinking agent and a liquid medium. The product exhibits areversible phase transition function that results in a drastic volumechange in response to changes of the liquid medium compositiontemperature or ion concentration.

[0015] U.S. Pat. No. 5,525,334 discloses a method for vascularembolization by introduction of an aqueous solution of a thermosensitivepolymer which gels in vivo at the body temperature of a patient.Obviously, such a thermosensitive gelling response will be inoperativein a process wherein the polymer must travel a substantial distancewithin the patient's body prior to gelation (such as when the gel isintroduced through a catheter running from the femoral artery to thebrain).

[0016] PCT published application number WO 99/56783 discloses a hydrogelfor the treatment of aneurysms, whereby the gel carries both aradiopaque agent (permitting the radiogel to be visualized underfluoroscopy) and a therapeutic agent. The hydrogel is delivered througha catheter into an aneurysm, where the hydrogel becomes more viscousupon reaching body temperature or upon exposure to bodily fluids. Thegelled compound blocks flow into the aneurysm, and can be adapted todeliver a human growth factor to promote growth of a cellular layeracross the neck of the aneurysm.

[0017] It is therefore an object of the present invention to provide asingle injectable aqueous gelling solution that is sensitive to at leasttwo environmental stimuli, and more preferably, a compound that issensitive to at least two in vivo environmental stimuli in a human orother mammalian body. The compound of the present invention will gelwhen exposed to critical minimum values of the environmental stimuli andis preferably a reversibly gelling compound, such that when the criticalminimum values of all (or at a minimum, at least one) of theenvironmental stimuli fall below or outside the range of sensitivity,the gelled compound returns to an un-gelled condition.

[0018] The ideal multiple stimulus reversible hydrogel comprises anaqueous-based solution or compound having low viscosity at formationconditions, but exhibits rapid gelation at physiological conditions. Itgels in response to multiple in-situ environmental stimuli, and isreversible. It must have reasonable mechanical strength and havebiocompatibility with the host tissue.

[0019] The following references disclose processes or compounds usefulin this art:

[0020] U.S. Pat. No. 5,525,334

[0021] U.S. Pat. No. 5,702,361

[0022] U.S. Pat. No. 5,695,480

[0023] U.S. Pat. No. 5,858,746

[0024] U.S. Pat. No. 5,589,568

[0025] T. G. Park and A.S. Hoffman, “Synthesis, Characterization, andApplication of pH/Temperature-sensitive Hydrogels”, Proceed. Intern.Symp. Control. Rel. Bioact. Mater., 17 (1990), pp 112-113.

[0026] G. Chen and A. S. Hoffman, “Graft Copolymers That ExhibitTemperature-induced Phase Transitions Over a Wide Range of pH”, Vol 3,Nature, 1995, pp. 49-52.

[0027] S. Beltran, J. P. Baker, H. H. Hooper, H. W. Blanch and J. M.Prausnitz, “Swelling Equilibria for Weakly Ionizable,Temperature-Sensitive Hydrogels”,Proc. Amer. Chem. Soc., 1991.

[0028] J. Zhang and N. A. Peppas, “Synthesis and Characterization of pH-and Temperature-Sensitive Poly(Methacrylicacid)/Poly(N-isopropylacrylamide) Interpenetrating Polymeric Networks,Macromolecules, 2000 (currently available on-line on the world wideweb).

[0029] T. G. Park, “Temperature Modulated Protein Release FrompH/Temperature Sensitive Hydrogels; Biomaterials 20 (1999), pp. 517-521.

SUMMARY

[0030] The present invention comprises an aqueous polymeric solutioncapable of gelling upon exposure to a critical minimum value of aplurality of environmental stimuli. A “plurality” of environmentalstimuli may be any number equal to or greater than two, although in mostcases the process of the present invention will utilize two stimuli. Theaqueous polymeric solution is capable of having gelation reversed ifall, or at a minimum, at least one, of the environmental stimuli fallbelow (or outside a range of) critical minimum values. The environmentalstimuli may be any stimulus that induces gelation, and is exemplified bytemperature, pH, ionic strength, electrical field, magnetic field,solvent composition, chemical composition, light, pressure and the like.The critical minimum values for each of these stimuli may vary dependingupon the local environment in which the gel is used, and will likely bemarkedly different between medical (or, in vivo) and industrial uses.

[0031] In vivo environmental stimuli may be either associated with humanpatients, or in veterinarian use with domestic or farm animals. Forexample, the product and process of the present invention may be usedwith cattle, horses, sheep, pigs, dogs, cats, and the like. Theenvironmental stimuli may be either conditions that are naturally foundwithin the area of use (e.g. “ambient”), or they may be externallyimposed. Generally speaking, when injected into a human, the aqueouspolymeric solution of the present invention is injected into a specificlocus within the body—either a cavity (such as a post-operative tumorsite) or a conduit/duct (such as a blood vessel) or into a tissue mass(such as a tumor).

[0032] The polymeric solution may either be a carrier for apharmaceutically active therapeutic agent (in which case it willtypically be an aqueous solution), or it may merely act as an inertblocking mass. An example of the former is the injection of chemicals orradioisotopes delivered through a catheter to a tumor mass; an exampleof the latter is injection of a gelled mass into a tubular body so as tocause a restriction therein (e.g. an aneurism of a blood vessel or thevas deferens for purposes of reversible sterilization in males).Likewise, the polymeric solution may be used in industrial situationswherein it may not be an aqueous solution.

[0033] It would be of great medical benefit in in vivo environments, ifan aqueous polymeric solution could be transported in a catheter withinthe body for extended distances without gelation. For example, if it isdesired to implant a quantity of radioisotope in a gelled mass withinthe brain, a catheter may be inserted into the patients femoral arteryand the therapeutic agent is transported from that locale to the brain.Through use of the process of the present invention, for example, thetwo stimuli to induce gelation may be temperature and pH in the bloodstream, such that warming of the liquid polymeric compound alone (withinthe catheter) will not cause gelation. It is not until the compoundcontacts the blood in the brain, and is induced by the pH or ionicstrength of the blood to gel, that gelation occurs.

BRIEF DESCRIPTION OF THE DRAWINGS

[0034]FIG. 1 is a graphical representation of the logarithm of storageviscosity (log n′) versus temperature for poly(NIPAAm-co-DMAEA) polymer;

[0035]FIG. 2 is a graphical representation of the storage modulus (G′)versus temperature for poly(NIPAAm-co-DMAEA) polymer;

[0036]FIG. 3 is a graphical representation of the complex viscositylogarithm (log n*) versus temperature for poly(NIPAAm-co-DMAEA) polymer;

[0037]FIG. 4 is a graphical representation of the storage viscositylogarithm (log n′) versus temperature for poly(NIPAAm-co-AAc) polymer;

[0038]FIG. 5 is a graphical representation of the storage modulus (G′)versus temperature for poly(NIPAAm-co-Aac) polymer; and

[0039]FIG. 6 is a graphical representation of the complex viscositylogarithm (log n*) versus temperature for poly(NIPAAm-co-Aac) polymer.

DETAILED DESCRIPTION

[0040] The reversible, stimulus-sensitive gels of the present inventionare intended primarily for use in medical environments, such as theembolization of blood vessels at remote anatomical locations. However,it is to be understood that the gels of the present invention are notlimited to medical applications—they will find uses outside medicine.For example, uses as drilling muds in the drilling of oil or other deepwells; subterranean use to block transport of noxious pollutants in anaquifer; the sealing of any industrial conduit to block passage ofmaterials therein, and the like.

[0041] There are specific uses of gelling polymers wherein it is greatlypreferred that the gelation response occur only when the polymersolution is exposed to multiple stimuli. As used herein, the stimuli maybe any environmental stimulus that, in combination with at least oneadditional stimulus, causes the gelation reaction of a polymer solution.For example, such stimuli as temperature, pH, ionic strength, electricalfield, magnetic field, solvent concentration/composition, surroundingchemical concentration/composition, light or pressure. While it isprobably preferred in most cases that gelation result from two stimuli,it is within the context of the present invention that gelation occur inresponse to three or more stimuli.

[0042] As used herein, the stimuli responsible for gelation must reach a“critical minimum value” to effectively cause gelation. Values outsideof this critical minimum value will cause the polymer composition toflow as (or similar to) a liquid. The critical minimum value will dependupon the particular environment—and the value for a single stimuli (forexample, temperature) may be radically different depending upon the use.For example, in the context of a polymer solution injected into theblood stream of a human body wherein temperature and pH are the stimuliresponsible for gelation, the critical minimum value for temperature isapproximately 35-37° C. (internal body temperature) and the criticalminimum value for pH is approximately 7.0-7.5 (the pH of blood and manyother interstitial fluids). On the other hand, the critical minimumvalue for gelation in oil-field applications may be in excess of 70° C.and pH of less than 6.0 or greater than 8.0. For ease of description,and as described herein, any stimuli condition that falls outside thatrequired for gelation is denoted as “below” or “less than” the criticalminimum value, even though the value may be higher. For example, whileroom temperature may be on the order of 20° C. and therefore below thecritical minimum value (37° C.) to induce gelation, a temperature of 50°C. may likewise inhibit gelation because it is too high, and as definedherein is also “below” the critical minimum value.

[0043] Gelation is the change in viscosity from a fluid-like compositionto a solid-like composition. While the degree of “solidness” may varyfrom application to application, generally speaking gels of the presentinvention will exhibit viscosities in the full range of from paste-liketo solid-like.

[0044] In certain situations, it is critical that gelation of the gel bereversible. For example, the pre-operative embolization of vessels fortumor treatment may be necessary to successfully shrink such tumors; itis not desired that blood flow be forever blocked in such vessels due tosevere tissue damage. Upon return to environmental stimuli conditionsthat are “below” the critical minimum values, the gel reverses itsviscosity and returns to a solution that is transportable within itsimmediate environment. The gels of the present invention are highlystable and do not exhibit phase separation upon standing or uponrepeated cycling between the liquid and gel state. It is especiallyimportant that once gelled in situ, that the gel composition remaingelled indefinitely, or until intentionally reversed. For example, it isanticipated that gels of the present invention can be designed that willremain gelled for as long as many years.

[0045] Also, as used herein, the word “environmental” refers to themyriad of stimuli that might induce gelation. In industrial, non-medicalsettings such environmental stimuli may comprise chemical composition,temperature, light, pressure, and the like. In the context of human orother mammalian bodies, the word “environmental” typically refers towell-known conditions within the body that can impact the gel(temperature, pH, ionic strength, etc.).

[0046] The polymers useful in the present invention include but are notlimited to thermally reversible copolymers that are useful as a gel thatforms without substantial syneresis when the thermally reversiblecopolymer is in an aqueous solution. Syneresis is defined as waterexpelled from a copolymer matrix upon gelation. Substantial syneresis ismore than about 10 wt % water expelled from the copolymer matrix.According to the present invention, it is preferred that the syneresisbe less than about 10 wt %, more preferably less than about 5 wt % andmost preferably less than about 2 wt %. Substantially no syneresis issyneresis of less than about 2 wt %, preferably 0 wt %.

[0047] As an example of the sort of polymers that can be synthesizedaccording to the present invention, and not intending to be limited bythe recitation of specific compounds, the thermally reversible copolymercan be a linear random, block or graft copolymers of an[meth-]acrylamide derivative and a hydrophilic comonomer wherein thecopolymer is in the form of a plurality of chains having a plurality ofmolecular weights greater than or equal to a minimum geling molecularweight cutoff. According to the present invention, the minimum gelingmolecular weight cutoff is at least several thousand and is preferablyabout 12,000. The presence of a substantial amount of copolymer orpolymer chains having molecular weights less than the minimum gelingmolecular weight cutoff results in a milky solution that does not gel.Further, the amount of hydrophilic comonomer in the linear randomcopolymer is preferably less than about 10 Mole %, more preferably lessthan about 5 Mole % and most preferably about 2 Mole %. When thehydrophyllic comonomer is AAc and the thermosensitive co-monomer isNiPAAm, the amount of AAc in the linear random copolymer is preferablyfrom about 1 mole % to about 2.5 Mole %, most preferably from about 1.6Mole % to about 1.9 Mole %. The structure of linear chains is not crosslinked. Moreover, the block or graft copolymer structure is one in whicha linear chain is shared by randomly alternating portions of the[meth-]acrylamide derivative and the hydrophilic comonomer.

[0048] The [meth-]acrylamide derivative is an N-alkyl substituted[meth-]acrylamide including but not limited toN-isopropyl[meth-]acrylamide, N,N-diethyl[meth-]acrylamide,N-[meth-]acryloylpyrrolidine, N-ethyl[meth-]acrylamide, and combinationsthereof.

[0049] The hydrophilic comonomer is any hydrophilic comonomer thatco-polymerizes with the [meth-]acrylamide derivative. Preferredhydrophilic comonomers are hydrophilic [meth]acryl-compounds includingbut not limited to carboxylic acids, [meth-]acrylamide, hydrophilic[meth-]acrylamide derivatives, hydrophilic [meth-]acrylic acid esters.The carboxylic acid may be, for example, acrylic acid, dimer of acrylicacid, methacrylic acid and combinations thereof. The hydrophilicacrylamide derivatives include but are not limited toN,N-diethyl[meth-]acrylamide,2-[N,N-dimethylamino]ethyl[meth-]acrylamide,2-[N,N-diethylamino]ethyl[meth-]acrylamide, or combinations thereof. Thehydrophilic [meth-]acrylic esters include but are not limited to2-[N,N-diethylamino]ethyl[meth]acrylate,2-[N,N-dimethylamino]ethyl[meth-]acrylate, and combinations thereof.

[0050] The polymer composition most likely having primary application inmedical applications is a hydrogel, wherein water is the solvent.Obviously, introducing non-aqueous solvents into a human or othermammalian body can have significant side effects. However, in industrialsettings, the solvent may comprise any well-known organic solvent.

[0051] In medical applications, the gels of the present invention may beutilized to deliver therapeutic agents to various body locations,including but not limited to intravenous and subcutaneous therapies,tissue supplementation, parenteral delivery, vascular and therapeuticembolization, tumor therapy, blockage of bodily conduits, and the like.Any biologically active compound having therapeutic qualities may bedelivered by the process of the present invention, including but notlimited to proteins, polypeptides, polynucleotides, polysaccharides,glycoproteins, lipoproteins, and the like.

[0052] Classes of therapeutically active or diagnostic compounds thatwill most likely be administered by the process of the present inventioninclude but are not limited to anti-cancer drugs, radionuclides,antibiotics, immunosuppressants, neurotoxins, antiinflammatory agents,imaging agents, and the like.

[0053] It is to be understood that while the biological uses of theproducts and processes of the present invention will find particularapplication with humans, other types of animals may be similarlytreated. Because the cost of these procedures is relatively expensive,they typically will not be useful in a commercial sense with a broadrange of animals. However, research applications of this technology withnon-mammalians may be feasible. Other than humans, the invention willfind particular application with cattle, horses, sheep, pigs, dogs,cats, and the like.

[0054] Generally speaking, compositions of polymers of the presentinvention will be found in very broad ranges. A reversible gelingsolution may be made by mixing the reversible polymer with an aqueoussolution in an amount of about 70 wt % to 99 wt %.

EXAMPLE 1

[0055] N-isopropylacrylamide was recrystallized from n-hexane and driedunder vacuum. Acrylic acid was distilled under reduced pressure.2.2′-azobisisobutyronitrile was purified by recrystallization frommethanol. Dioxane was sonicated, degased and purged with deoxygenatednitrogen prior to use. Either nad hexane (reagent grade) were used asreceived. Phosphate-buffered saline (PBS) (pH=7.4) was made bydissolving 0.272 g of anhydrous KH₂PO₄, 2.130 g of Na₂HPO₄ xH₂O and8.474 g of NaCl in 1.0 liter of ultra-pure water. pH of the solution wasadjusted to 7.4 with ORION 720A pH-meter.

[0056] The copolymers were obtained by free-radical solutioncopolymerization of N-isopropylacrylamide (NIPAAm) with a propercomonomer; 2-(dimethylamino)ethyl acrylate (DMAEA) for KK- 11copolymerand acrylic acid (Aac) for Mj-114 copolymer. A positively ionizable,weakly basic copolymer was synthesized in dioxane, using 97/3 mol %ratio of NIPAAm and DMAEA, using AIBN as a free-radical initiation. Themonomers (5.000g, 4.415×10⁻² moles of NIPAAm and 207.3uL, 1.365×10³¹³moles of DMAEA) were dissolved in dry, degassed dioxane (24 mL) andflushed with dry, deoxygenated nitrogen for 0.5 hour. After adding AIBN(4.8 mg, 2.93×10−5 moles in dioxane solution (about 100 uL), the mixturewas purged with nitrogen for additional 10 minutes. The polymerizationwas conducted at 70° C. for 19 hr under pure nitrogen. The reactionmixture was then cooled to RT, diluted with dioxane (24mL), poured into3/1 v/v mixture of ethyl ether/hexane and vigorously stirred for about 2hours. The crude polymer was then filtered, washed with ether and driedin vacum overnight. Dry polymer was dissolved in 200 mL of UP water andfiltered through a nylon membrane (pore size 0.45um). Crude polymersolution was purified by ultrafiltration (three times) using a 30KD MWCOmembrane. The purified solution was freeze-dried to obtain a dry polymerpowder (yield 84-85%).

[0057] The molar masses were analyzed by Gel Permeation Chromatography(GPC), using the following equipment:

[0058] two styragel columns, HMW 6E and HR 4E (7.8×300 mm both);

[0059] Rheodyne 50 or 200 ul loop injector;

[0060] Detectors: miniDAWN light scattering detector and Waters 410Differential Refractometer;

[0061] 515 HPLC Waters pump and isocratic THF (HPLC grade) mobile phase,sonicated and degassed; flow rate was set at 0.5 ml/min;

[0062] Astra 4.70 software.

[0063] The results are summarized in Table 1 below. TABLE 1 Molar massanalysis by gel permeation chromatography Sample Average MolarPoydispersity ID Polymer ID mass (M_(w)), g/mol (M_(w)/M_(n)) MJ-114poly(NIPA-co-AAc) 1.14 ± 0.03 e+05 1.024 ± 0.04 KK-11 poly(NIPA-co-DMAEA) 6.37 ± 0.48 e+05  1.05 ± 0.08

[0064] Reversible sol-gel transitions of the poly(NIPAAm-co-DMAEA) andpoly(NIPAAm-co-Aac) polymer solutions were studied using dynamicrheology (Rheometric Scientific SR 2000). The polymer solutions wereplaced between parallel plates with diameter 2.5 mm and gap 0.5mm. TheDynamic Temperature Ramp Test (DTRT) was conducted under controlledstress (2.0 dync/cm²) and frequency (1.0 radian/sec.). Theheating-cooling cycle temperature gap was established for 21-37° C. withincrement 0.3° C. A 10% polymer solution in water and PBS wasinvestigated.

[0065] FIGS. 1-6 illustrate the results of DTRT conducted forpoly(NIPAAm-co-DMAEA) and poly(NIPAAm-co-AAc) polymer solutions attemperature gap 21-37° C. FIG. 1 illustrates changes in the log of thestorage viscosity (n′) of poly(NIPAAm-co-DMAEA) (KK- 11) polymersolution as a function of temperature. Heating process (H) causes sol togel transition and, as a result, viscosity increases by three orders ofmagnitude (0.1-100 Pa×s). The increase is very sharp and takes place atabout 34-36.5° C. Upon cooling (C), the gel melts at a temperature thatis lower than the gelation temperature indicating characteristichysteresis loop between gel formation and gel melting temperatures. Thisbehavior results from resistance to disintegration of entangled hydrogelmolecules. This experiment was conducted under controlled stress (2.0dyne/cm²) and frequency (1.0 radian/sec). The heating-cooling cycletemperature increment was 0.3° C. FIG. 2 illustrates how the storagemodulus changes as a function of temperature, under controlled stress(2.0 dyne/cm²) and frequency (1.0 radian/sec). The heating-cooling cycletemperature increment was 0.3° C. FIG. 3 illustrates the logarithm ofcomplex viscosity changes as a function of temperature, conducted undercontrolled stress (2.0 dyne/cm²) and frequency (1.0 radian/sec). Theheating-cooling cycle temperature increment was 0.3° C.

[0066] FIGS. 4-6 illustrate rheological behavior of poly(NIPAAm-co-Aac)(MJ 114k) polymer solution. Each of the experiments of FIGS. 4-6 wereconducted under controlled stress (2.0 dyne/cm 2) and frequency (1.0radian/sec.). The heating-cooling cycle temperature increment was 0.3°C.

[0067] The properties illustrated in FIGS. 1-6 illustrate the benefitsof the instant invention. A sharp sol to gel transition takes place justbefore the physiological temperature of the human body, and hysteresishelps to avoid quick melting of the formed gel due to small fluctuationsof body temperature. The storage modulus (G′) of two gels is practicallyzero at a sol state, so it is not shown on a heating curve. It appearsand sharply increases at 32.0 and 32.5° C. for poly(NIPAAm-co-Aac) andpoly(NIPAAm-co-DMAEA) gels solutions in PBS, as shown in FIGS. 2 and 5respectively. For both gels, the maximum value of the storage modulus isat about 37° C., indicating that the material is susceptible forinjectable gelling formulations.

[0068] Different behavior of the polymer solutions in water versus thosein PBS proves that it is possible to deliver the water solution to aremote anatomical location via a long needle or catheter in a sol(non-gelled) state. The polymer water solution will gel upon contactwith body fluids at physiological temperature.

EXAMPLE 2

[0069] A copolymer of N-isopropylacrylamide with hydrophilic comonomer,2(dimethylamino)ethyl acrylate (DMAEA) was synthesized in dioxane by afree radical polymerization. After a two-step extensive purification, byprecipitation and ultrafiltration the NDAEA copolymer was lyophilized toobtain the copolymer in a powder form. This powder was then dissolved inwater to form an aqueous solution.

[0070] A 2 ml sample of this solution, warmed up to 37° C., was placedin a 2 ml syringe equipped with a 30 Gauge needle. The needle wasimmersed in a phosphate buffered saline (PBL) solution also warmed up to37° C. The warm copolymer solution from the syringe was injected intothe warm PBS solution. Instantaneous gel formation was observed; theinjected gel formed a “string”.

[0071] An additional 2 ml sample of the same aqueous solution was heatedgradually from room temperature up to 40° C. No gel formation wasobserved even at 40° C.

[0072] Yet another 2 ml sample of the same solution, equilibrated atroom temperature, was placed in a 2 ml syringe equipped with a 30 Gaugeneedle. The needle was immersed in a phosphate buffered saline (PBs)solution also equilibrated at room temperature. The room temperaturecopolymer solution from the syringe was injected into the roomtemperature PBS solution. No gel formation was observed—the injectedpolymer solution simply dissolved in the buffer.

[0073] Thus, the impact of multiple stimulus gelation is evident intemperature and proper ionic strength is required to cause gelation ofthe NDAEA copolymer. Change in only one stimuli was ineffective to causegelation.

EXAMPLE 3

[0074] A copolymer of N-isopropylacrylamide with hydrophilic comonomer,2-(N,N-dimethylamino)ethyl acrylate (NDAEA) was synthesized in dioxaneby a free-radical polymerization. After a two-step extensivepurification, by precipitation and ultrafiltration, the NDAEA copolymerwas lyophilized to obtain the copolymer in powder form. This powder wasthen dissolved in water to form an aqueous solution.

[0075] A 2 ml sample of this solution, warmed to 37° C., was placed in a2 ml syringe equipped with a 30 Gauge needle. The needle was immersed ina PBS solution also warmed up to 37° C. The warm copolymer solution fromthe syringe was injected into the warm PBS solution. Instantaneous gelformation was observed, the injected gel forming a “string”. Another 2ml sample of the same aqueous solution was heated gradually from roomtemperature up to 40° C. No gel formation was observed even at 40° C.

[0076] Yet another 2 ml sample of the solution, equilibrated at roomtemperature, was placed in a 2 ml syringe equipped with a 30 Gaugeneedle. The needle was immersed in a PBS solution also equilibrated atroom temperature. The room temperature copolymer solution from thesyringe was injected into the room temperature PBS solution. No gelformation was observed; the injected polymer solution simply dissolvedin the buffer.

Closure

[0077] Having thus described a preferred exemplary embodiment of thepresent invention, it should be noted by those skilled in the art thatthe disclosures herein are exemplary only and that alternatives,adaptations and modifications may be made within the scope of thepresent invention. Thus, the present invention is not to be limited tothe specific embodiments illustrated herein, but solely by the scope ofthe claims appended hereto.

I claim:
 1. A polymeric solution capable of gelling upon exposure to acritical minimum value of a plurality of environmental stimuli, saidpolymeric solution capable of having gelation reversed if at least oneof such environmental stimuli fall below said critical minimum value. 2.The compound of claim 1, wherein the plurality of environmental stimuliare selected from the group consisting of temperature, pH, ionicstrength, electrical field, magnetic field, solvent composition, light,pressure and chemical composition of the ambient environment.
 3. Thecompound of claim 1, wherein gelation occurs upon exposure to at leasttwo ambient environmental stimuli.
 4. The compound of claim 1, whereingelation occurs upon exposure to a critical minimum value of twoenvironmental stimuli.
 5. The compound of claim 1, wherein gelationoccurs upon exposure to at least two in vivo environmental stimuli. 6.The compound of claim 1, wherein gelation occurs upon exposure to atleast two in vivo environmental stimuli that are imposed externally. 7.The compound of claim 1, wherein the plurality of environmental stimuliare in vivo conditions found in a human body.
 8. The compound of claim1, wherein the plurality of environmental stimuli are in vivo conditionsfound in non-human mammalian bodies.
 9. The compound of claim 1, whereinthe compound is injected into a specific locus in a human body.
 10. Thecompound of claim 9, wherein the compound includes a therapeuticallyactive agent for treatment of a medical condition.
 11. The compound ofclaim 10, wherein the compound includes a radioisotope for treatment ofa medical condition.
 12. The compound of claim 10, wherein the compoundis injected into a tubular conduit so as to cause a blockage therein.13. The compound of claim 12, wherein the compound is injected into ananeurysm in a blood vessel.
 14. A method of forming a reversible gelfrom an aqueous polymeric solution, comprising the step of exposing theaqueous polymeric solution to a critical minimum value of a plurality ofenvironmental stimuli to form a gel, said gel capable of being reversedto said aqueous polymeric solution by reducing the value of more thanone of the environmental stimuli below a critical minimum value.
 15. Themethod of claim 14, further comprising selecting the environmentalstimuli from the group consisting essentially of temperature, pH, ionicstrength, electrical field, magnetic field, solvent compositions,chemical compositions, light and pressure.
 16. The method of claim 14,further comprising exposing the environmental stimuli in vivo within amammalian body.
 17. The method of claim 14, further comprising providingthe environmental stimuli externally from outside the mammalian body.18. The method of claim 14, further comprising injecting the aqueouspolymeric solution into a specific locus in the human body.
 19. Themethod of claim 14, further comprising injecting the aqueous polymericsolution into an embolization in a blood vessel.
 20. The method of claim14, further comprising placing a therapeutically active agent fortreatment of a medical condition into the polymeric compound.
 21. Themethod of claim 14, further comprising placing a radioisotope fortreatment of a medical condition into the polymeric compound.
 22. Themethod of claim 1, further comprising providing said polymeric solutionas an aqueous solution.
 23. The method of claim 14, further comprisingproviding a [meth]acrylamide and suitable hydrophobic comonomer.
 24. Themethod of claim 14, further comprising providing the polymeric solutionas an aqueous solution.
 25. The method of claim 24, further comprisingproviding said polymer as a comonomer of 2-(dimethylamino)ethyl acrylate(DMAEA) and N-isopropylacrylamide.
 26. An aqueous polymeric solutioncapable of gelling upon exposure to a critical minimum value of at leasttwo in vivo environmental stimuli, said aqueous polymeric solutioncapable of having gelation reversed if more than one of such in vivoenvironmental stimuli fall below said critical minimum value.
 27. Amethod of forming a reversible gel from an aqueous polymeric solution,comprising the step of exposing the aqueous polymeric solution to acritical minimum value of at least two in vivo environmental stimuli toform a gel, said gel capable of being reversed to said liquid polymericcompound by reducing the value of more than one of the in vivoenvironmental stimuli above a critical minimum value.